Lazarus type response to immunotherapy in three patients with poor performance status and locally advanced NSCLC: a case series and literature review

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients with this lung cancer present with advanced, unresectable disease on diagnosis (1,2), and nearly 34% of patients have a poor performance status (PS) (PS: 2–4) (3). Due to the lack of effective treatments, most PS ≥3 patients die within 2–4 months from the date of diagnosis (4). However, studies have reported that targeted therapy is efficacious in patients with poor PS, and even a Lazarus response has been observed in those patients with oncogenic drivers (5,6). In modern medical parlance, the Lazarus-type response refers to an event in which a person miraculous recuperate from near death. Just as in the new testament of the Bible, Jesus raised Lazarus of Bethany from the dead (7).

Immunotherapy with immune checkpoint inhibitors (ICIs), including those targeting programmed cell death 1 (PD-1), or programmed cell death protein ligand-1 (PD-L1) has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) in patients without oncogenic drivers (8). Four phase III randomized trials have shown that ICIs such as nivolumab, atezolizumab and pembrolizumab significantly improve overall survival (OS) and progression-free survival (PFS) when compared with standard chemotherapy (9-11). PD-L1 expression in tumor cells and tumor mutation burden (TMB) has been the main predictive biomarker for ICIs efficacy in NSCLC (11,12). Pembrolizumab monotherapy regimens reported an incidence of grade III–IV treatment-related adverse events (TRAEs) of 15–30%, while nivolumab monotherapy revealed a grade III–IV TRAEs incidence of 10% (13,14). The most frequent potential immune related adverse events (irAEs) of anti-PD-1 therapies involved rash, pruritus, colitis, diarrhea, hyperthyroidism, hypothyroidism, lymphopenia, hepatitis, et al. These drug-related adverse events are well tolerated and manageable in most patients with Eastern Cooperative Oncology Group (ECOG) PS 0–1 (15).

Patients with PS ≥2 are usually excluded or underrepresented in clinical studies, and thus there is little data available on the safety and efficacy of immunotherapy in this population (16,17). In the four published prospective trials that have included PS ≥2 patients, the incidence of grade 3–4 irAEs was similar, while OS was worse compared with the overall population (18-21). For NSCLC patients who are critically ill or have PS 3–4, there are currently no dedicated ongoing trials, and few real-world case reports exist on the role of ICIs in patients with PS 3–4. Roesel et al. reported two cases of patients with lung sarcomatoid carcinoma and high PD-L1 expression, one of which presented with progressive dyspnea accompanied by hypoxemic respiratory insufficiency. Immunotherapy with nivolumab was initiated, which resulted in fast and extensive tumour regression and relief of tumour symptoms (22). The safety and efficacy of ICIs when administered to patients who are critically ill or have very poor PS (3,4) remain controversial and largely unexplored. In this study, we describe a group of three severe (locally) advanced NSCLC patients with PD-L1 expression over 50% successfully treated with anti-PD-1 immune checkpoint monoclonal antibodies, and showed rapid symptom relief and lesion response (Table 1).

Table 1 Patients and tumor characteristics
Full table

We present the following article in accordance with the AME Case Series Checklist (available at http://dx.doi.org/10.21037/apm-20-2279).

Methods

Study design

We reviewed clinical data retrospectively from three patients with poor PS and (locally) advanced NSCLC who received immunotherapy in Daping hospital (Chongqing, China). Data collected from the patient’s electronic medical record included: age, sex, ECOG PS, oxygenation index (OI), tumor histology, and drugs for PD-1/PD-L1 blockade. Data regarding PD-L1 expression, and tumor mutation burden were analyzed. Treatment decision was made according to the National Comprehensive Cancer Network (NCCN) Guideline and local guidelines for NSCLC. The patients described herein provided written informed consent. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethical board of the Daping Hospital, Army Medical University [No.: 2020(163)].

Statistical analysis

Descriptive statistics were used to summarize patients and disease characteristics. The primary outcome was time-to-response, efficiency, rate of ECOG PS recovery, and safety. Response to treatment was determined by using Response Evaluation Criteria in Solid Tumor (RECIST), version 1.1. PFS was defined as the interval from the date of first pembrolizumab administration to the date of radiological/clinical progression or death due to any cause, whichever occurred first, or to the date of last follow-up visit for patients alive without disease progression. OS was defined as the interval from the date of first pembrolizumab administration to the date of death or to the date of last follow-up for alive patients.

Results

Case 1

Patient 1 was a 63-year-old male smoker, who presented with severe dyspnea, reversal fever, and hemoptysis. Bronchoscopy revealed that the squamous cell carcinoma had invaded the tracheal carina (Figure 1A,B). The chest computed tomography (CT) scan showed lesions in the left lung with partial atelectasis (Figure 1C), and thus the clinical stage was determined to be IIIc (cT4N3M0, American Joint Committee on Cancer, 8th edition). Due to severe pulmonary infection (white blood cell 26.52×10⁹/L neutrophil 92.6%) and respiratory failure with an OI of 180, the patient received oxygen therapy, antibiotics (imipenem, 1 g, q8h, ivgtt), and hemostatic drugs. After 1 week, the patient developed severe hemoptysis (100–150 mL/day) and respiratory distress (OI 120), although the fever was controlled. Chest X-ray revealed atelectasis of the left lung (Figure 1D). Tissues were examined for the expression of PD-L1 and TMB and were collected at the time of the diagnosis. However, the patient was weakened with a PS of 4 before the start of treatment. Due to strong PD-L1 expression levels (80%, 22C3 antibody) (Figure 1E), the patient received treatment with pembrolizumab (200 mg) every 3 weeks beginning March 12, 2019. One day after the initiation of pembrolizumab, dyspnea was relieved. The OI was improved to 310 two days later. The left lung atelectasis was partially relieved, and a PS score of 4 improved to 1 within the span of less than 1 week (Figure 1F). After two cycles of pembrolizumab, a rapid tumor partial response was obtained. The left lung atelectasis was completely relieved without the need of intervention therapy (Figure 1G). Bronchoscopy revealed that there were no neoplasms in the mainstem bronchus (Figure 1H). Meanwhile, the CT scan showed over 60% reduction in the size of left hilar mass (Figure 1I). Treatment-related side-effects were not observed during the treatment. After 18 cycles of pembrolizumab and when the lesion was stable, radiotherapy was successfully finished. The patient has continued with treatment of pembrolizumab, and his improvements on clinical and radiographic examination have continued as of the latest follow-up (Figure 1J).

Figure 1 Graphic summary of patient 1. (A) A neoplasm (white arrow) obstructing the left mainstem bronchus was found by bronchoscopy (baseline). (B) Hematoxylin-eosin (HE) staining of tissue sample from patient 1 revealed squamous cell carcinoma of the lung. (C) CT scans revealed lesions (red arrow) in the left lung with partial atelectasis. (D) Chest X-ray revealed atelectasis of the left lung before starting pembrolizumab. (E) Programmed death-ligand 1 (PD-L1) was found positive (80%) using immunohistochemistry (IHC, 22C3, Dako; ×200). (F) After initiating pembrolizumab treatment, the left lung atelectasis was partially relieved within the span of less than 1 week. (G) Three weeks later, the left lung atelectasis was completely relieved. (H) No neoplasm (white arrow) was found by bronchoscopy after four cycles of pembrolizumab. (I) A computed tomography (CT) scan showed about 60% reduction in the size of the left hilar mass (red arrow) after two cycles of pembrolizumab. (J) The latest findings of CT scans showed partial response of the primary tumor (red arrow). i, performance status (PS) evolution over time; ii, timeline of therapies OI improved rapidly after initiating pembrolizumab. OI, oxygenation index.

Case 2

A 70-year-old man was diagnosed with stage IV lung adenocarcinoma of the right lower lobe associated with left frontal lobe, right pleural, and multiple bone metastasis (Figure 2A,B,C). After one cycle of cytotoxic drug regimens (carboplatin plus pemetrexed), pleural effusion was increased and encapsulated, which made it difficult to drain (Figure 2D,E). More seriously, the patient developed arrhythmias (atrial fibrillation and tachycardia) related to chemotherapy. Clinical symptoms such as pain, dyspnea, and cough deteriorated with time. The patient was forced to sleep on the right side, and the OI was only 150. Prior to the second line of therapy, the PS score of the patient was 4. Owing to the high tissue TMB (13.71 muts/Mb) and strong PD-L1 expression (50%, 28–8 antibody) of the tumor (Figure 2F), the patient was started on a regimen of nivolumab (140 mg) every 2 weeks beginning August 30, 2018. On that day of intravenous infusion of nivolumab, the patient could sleep his the left side and dyspnea was relieved. On day 3 after administration of nivolumab, his PS score rapidly improved to 1, and the OI was increased to 310. Reexamination with X-ray showed that pleural effusion had reduced (Figure 2G,H). After two cycles of nivolumab, although the lesions were stable on CT scan, clinical symptoms of the patient were obviously relieved. After 3 months (6 cycles of ICIs), a marked response was observed with an apparent reduction of the primary tumor, brain metastasis, and pleural effusion (Figure 2I,J). ICI-related rash (grade 2 irAE) and hypothyroidism (grade 2 irAE) occurred. Betamethasone ointment and thyroxine tablets were used to handle with irAEs. Maintenance ICIs have continued as of the time of writing, (June 14, 2020), and the lesions are still slowly shrinking (Figure 2K).

Figure 2 Graphic summary of patient 2. (A) Magnetic resonance imaging (MRI) of the brain revealed a left frontal lobe (white arrow) metastasis. (B) CT scans showed an extensive mass (red arrow) in the right lung. (C) HE staining of tissue sample from patient 2 revealed adenocarcinoma of the lung. (D,E) Chest X-ray revealed that pleural effusion was increased and encapsulated after chemotherapy. (F) PD-L1 was found positive (50%) using immunohistochemistry (IHC, 28-8, Dako; ×200). (G,H) Pleural effusion was reduced after initiating nivolumab. (I,J) The size of the lesions in the right lung (red arrow) and brain (white arrow) were reduced after six cycles of nivolumab. (K) The latest findings of computed tomography (CT) scans showed partial response of the primary tumor (red arrow). i, performance status (PS) evolution over time; ii, timeline of therapies. OI improved rapidly after initiating pembrolizumab. OI, oxygenation index.

Case 3

The patient was a 75-year-old female who complained of severe dyspnea with an OI of 146. As for her breathing state, oxygen saturation (SpO₂) was around 90% under the conditions of an oxygen flow rate of 10 L/min with a reservoir bag mask. A Chest CT scan showed a huge mass on the right upper lobe which had invaded the mediastinum (Figure 3A). Bronchoscopy showed a neoplasm completely obstructing the right mainstem bronchus. Finally, the patient was diagnosed with lung squamous cell carcinoma (cT3N2M0, stage IIIb) (Figure 3B), and PD-L1 expression was 80% using the 28-8 antibody (Figure 3C). Prior to the initiation of treatment, the PS score of the patient was 4. The patient started to receive nivolumab (140 mg) every 2 weeks beginning September 14, 2018. After 3 days of treatment, dyspnea was relieved and OI was improved to 320. Although her PS score gradually improved to 1, the tumor size was only reduced by about 7% on CT imaging after three courses of ICIs (Figure 3D). The patient then began to receive six courses of nivolumab combined with chemotherapy (paclitaxel plus platinum), and finished lung radiotherapy. Reexamination with a CT scan showed partial response of the lung lesions (Figure 3E). The patient was able to continue maintenance therapy of nivolumab without any other adverse events. However, disease progression occurred on August 14, 2019. After this time, the patient only received symptomatic treatment due to financial constraints, and the patient died on January 14, 2020. The OS of the patient was 16 months.

Figure 3 Graphic summary of patient 3. (A) A computed tomography (CT) scan showed a large mass (red arrow) in the right lung (baseline). (B) HE staining of tissue sample from patient 3 revealed squamous cell carcinoma of the lung. (C) PD-L1 was found positive (80%) using immunohistochemistry (IHC, 28-8, Dako; ×200). (D) The tumor size (red arrow) was only slightly reduced after two cycles of nivolumab. (E) CT scans showed partial response of the lung lesions (red arrow) after administering six cycles of nivolumab + chemotherapy. i, performance status (PS) evolution over time; ii, timeline of therapies. OI improved rapidly after initiating pembrolizumab. OI, oxygenation index.

Discussion

The NCCN Guideline recommends only the best supportive care for patients with advanced NSCLC and poor PS (≥2) (23). Palliative care is considered an ineffective antitumor method, and thus patients treated with this approach have a very poor prognosis (4). Although targeted therapy based on molecular types has been reported to have successfully treated critically ill NSCLC patients, effective treatment strategies for patients without oncogenic drivers still need to be explored (24,25). Immunotherapy, including use of PD-1/PD-L1 inhibitors, has significantly improved the survival of advanced NSCLC patients without oncogenic drivers. The potential efficacy and favorable toxicity profile of ICIs make them an attractive option for NSCLC patients who are critically ill or who have poor PS. Although the U.S. Food and Drug Administration (FDA) authorization for using ICIs does not restrict the use of these drugs to PS 0–1 patients, the evidence for making treatment decisions about using ICIs in PS ≥2 patients are scarce and are derived mostly from heterogeneous meta-analyses or real-world studies (26,27). Therefore, there is still a need to apply rigorous clinical practice, with the aim of providing reliable data on the safety and effectiveness of immunotherapy in this special group.

We here report the cases of three (locally) advanced NSCLC patients presenting with critically ill or poor general condition (PS 4), who demonstrated rapid clinical improvement and a remarkable objective response from PD-1 blockade. The type of response has been dubbed the “Lazarus type” response, as it is similar to the miraculous resurrection of Lazarus in the New Testament of the Bible (5). The PS score of the three patients improved rapidly to 0–1 in a short time, which provided opportunities for other treatments, such as chemotherapy or radiotherapy. For all patients, next-generation sequencing (NGS) of the biopsied tissue lacked a targetable driver mutation, and intense PD-L1 expression was examined by immunohistochemistry of pretherapeutic biopsies. The first two cases achieved partial response (PR) and received prolonged benefits from single-agent immunotherapy, while the third case 3 obtained PR from combined use of chemotherapy after improvement of PS. At the time of writing, the first two patients are still alive, while the other patient died on January 14, 2020. This patient’s PFS and OS were 11 months and 16 months, respectively. The safety of ICIs was acceptable for all three patients, and there were no grade 3–4 irAEs. Only one patient experienced rash (grade 2 irAE) and hypothyroidism (grade 2 irAE) during immunotherapy.

Previous studies have confirmed that immunotherapy is safe and effective in NSCLC patients with a PS of 2 (18). The PePS2 trial revealed pembrolizumab to be safe in patients with a PS of 2. Similarly, the CheckMate 171 (19) and CheckMate 153 (20) trials with nivolumab showed no difference in the incidence of irAEs between the PS 2 and PS 0–1 populations (7% vs. 12% and 9% vs. 6%, respectively). However, the OS of PS 2 patients were shown to be worse compared with the overall population (5.2 vs. 9.9 months and 3.9 vs. 9.1 months, respectively). A retrospective analysis of the use of ICIs in patients with various cancers (including colorectal, small bowel, gastric, biliary tract, pancreatic, and endometrial cancers) with a PS of 2­–3 (patients with a PS of 3 accounted for 26% of the cohort) showed an overall manageable safety profile (28). For NSCLC patients with a PS of 3–4, immunotherapy was still found to be safe, although only a few cases have been reported (29,30). In short, ICIs are generally well tolerated, and the side effects are manageable in most cases (15). In clinical practice, few patients with poor PS receive ICIs as first-line therapy. Almost invariably, the poor PS is an independent factor for poor outcomes (31,32). Of note, patients with poor PS due to the disease burden itself were found to have a worse outcome compared to those with a poor PS due to comorbidities (33). For one, patients with a PS ≥2 show heterogeneity, which included old age, cachexia, organ dysfunction, systemic inflammation, comorbidity, etc., all of which may lead to shorter survival time (33). Moreover, the efficacy of ICIs may be weakened due to antibiotics and the dependency on supportive corticosteroids (34,35). Furthermore, a poor condition may diminish immune cell activity and thus reduce ICI efficacy (36).

Although there are no dedicated ongoing trials for PS 3–4 patients, Lazarus type responses to ICIs have still been observed in those patients with strong PD-L1 expression (≥50%), as was the case in the three patients in our report (29). Even in critically ill patients with mechanical ventilation, rapid and long-lasting responses have also been observed (30). Therefore, when it comes to the special population of patients with poor PS, the use of anti-PD-1/PD-L1 agents may be justified by virtue of their favorable toxicity profile and long-term efficacy. Thus, the identification of biomarkers is urgently needed to guide the treatment of ICIs.

Currently, the PD-L1 expression levels of tumors may offer a selection criterion for NSCLC patients to predict their immunotherapy response. The population with intense PD-L1 expression (≥50%) accounts for 29.8% of NSCLC cases (37). The Keynote 024 trial (38) has confirmed that pembrolizumab monotherapy is superior to system chemotherapy in the treatment of newly diagnosed advanced NSCLC with PD-L1 expression over 50%. The median PFS (mPFS) of the pembrolizumab treatment group was significantly longer than that of chemotherapy group (10.3 vs. 6.0 months), and a significant improvement in median OS (mOS) was also achieved in the ICI group (30.0 vs. 14.2 months). Meanwhile, the CheckMate 026 trial (39) revealed that nivolumab was better compared with cytotoxic chemotherapy for patients with a high TMB (>243 missense mutation/sample) (mPFS 9.7 vs. 5.8 months). It is worth noting that the objective response rate (ORR) of patients with PD-L1 ≥50% in the high-TMB subgroup was as high as 75%.

As expected, in the presence of a high PD-L1 expression and/or high tumor mutation burden, the PFS of ICI treatment was also longer in NSCLC patients with poor PS. A single-arm phase II trial of ECOG PS 2 NSCLC patients using pembrolizumab monotherapy, the PePS 2 trial, confirmed that the higher PD-L1 expression was, the more clinical benefits there were (18). The ORR for PD-L1 <1% (n=27), PD-L1 1–49% (n=15), and PD-L1 ≥50% (n=15) was 19%, 33% and 47%, respectively, while the mPFS was 3.3 months, 6.8 months, and 8.5 months, respectively. In addition, the CheckMate 817 trial, which included a cohort of special populations with advanced NSCLC (ECOG PS 2 or ECOG PS 0–1 with asymptomatic untreated brain metastases, renal or hepatic dysfunction, or human immunodeficiency virus infection), showed that nivolumab plus ipilimumab could prolong the mPFS of the PS 2 subgroup with high TMB (≥10 muts/Mb) compared to those with low-TMB (<10 muts/Mb) (8.3 vs. 2.8 months) (21).

Therefore, PD-L1 expression combined with TMB may be synergistic predictive biomarker for response to anti-PD-1/PD-L1 immunotherapy. In our report, all three patients presented strong PD-L1 expressions over 50%, and one of them had high TMB. It is suggested that ICI treatment should be considered for patients with severe lung cancer or/and poor PS score when strong PD-L1 expression or/and high-TMB are found in this special group. In clinical practice, immunotherapy is one of the most expensive anticancer treatments; especially if there is no sufficient experimental evidence in advanced NSCLC patients with poor PS, this approach of gamble oncology may incur severe financial hardship on patients, families, and society (40). Thus, relevant biomarkers are urgently needed to identify those patients with severe lung cancer who may derive potential benefits from immunotherapy.

However, some patients with rapid PS deterioration may miss the chance to receive ICIs. For first-line treatment, the median response time of monotherapy in the general population was found to be 2 months (41). Meanwhile, in patients with poor PS, the average response time for ICI treatment was found to be 3.1 months (28). In our report, the three patients treated with immunotherapy all demonstrated a rapid improvement of the symptoms and PS score, and two of them showed radiographic response in a short time. It is speculated that the onset time of immunotherapy may be positively correlated with the expression level of PD-L1 and TMB. However, more relevant studies are needed to support this view.

Conclusions

We described three critically ill or PS 4 (locally) advanced NSCLC patients with PD-L1 ≥50% who were successfully treated with anti-PD-1/PD-L1–based therapy. A Lazarus type response was observed in all patients. Both clinical symptoms and physical conditions showed rapid improvement. Although it is limited by its retrospective nature and small sample size, our report gives support to the safety and activity of ICI administration. The case series highlights that metastatic NSCLC patients who are critically ill or who have a poor PS score, immunotherapy, as opposed to best supportive care, is an effective and low-toxicity option. Those patients with high PD-L1 expression (≥50%) and/or high TMB may be best treated with salvage immunotherapy. More prospective studies are needed to identify reliable predictive biomarkers of efficacy and toxicity in advanced NSCLC patients with critical illness and/or a poor PS score.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the AME Case Series Checklist. Available at http://dx.doi.org/10.21037/apm-20-2279

Data Sharing Statement: Available at http://dx.doi.org/10.21037/apm-20-2279

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm-20-2279). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved ethics board of Daping Hospital, Army Medical University [No.: (2020)163]. Informed consent was obtained from the patient described in this case report.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7-30. [Crossref] [PubMed]
2. Brahmer JR, Govindan R, Anders RA, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of non-small-cell lung cancer (NSCLC). J Immunother Cancer 2018;6:75. [Crossref] [PubMed]
3. Lilenbaum RC, Cashy J, Hensing TA, et al. Prevalence of poor performance status in lung cancer patients: implications for research. J Thorac Oncol 2008;3:125-9. [Crossref] [PubMed]
4. Gounant V, Lavolé A, Quoix E. Ongoing challenges of using immunotherapy in special populations: Poor performance status patients, elderly patients, and people living with HIV. Lung Cancer 2020;145:71-5. [Crossref] [PubMed]
5. Shea M, Huberman MS, Costa DB. Lazarus-Type Response to Crizotinib in a Patient with Poor Performance Status and Advanced MET Exon 14 Skipping Mutation-Positive Lung Adenocarcinoma. J Thorac Oncol 2016;11:e81-2. [Crossref] [PubMed]
6. Liu S, Wang D, Chen B, et al. The safety and efficacy of EGFR TKIs monotherapy versus single-agent chemotherapy using third-generation cytotoxics as the first-line treatment for patients with advanced non-small cell lung cancer and poor performance status. Lung Cancer 2011;73:203-10. [Crossref] [PubMed]
7. Langer CJ. The "lazarus response" in treatment-naive, poor performance status patients with non-small-cell lung cancer and epidermal growth factor receptor mutation. J Clin Oncol 2009;27:1350-4. [Crossref] [PubMed]
8. Rashdan S, Gerber DE. Immunotherapy for non-small cell lung cancer: from clinical trials to real-world practice. Transl Lung Cancer Res 2019;8:202-7. [Crossref] [PubMed]
9. Horn L, Spigel DR, Vokes EE, et al. Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol 2017;35:3924-33. [Crossref] [PubMed]
10. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 2020;383:1328-39. [Crossref] [PubMed]
11. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1epositive nonesmall-cell lung cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
12. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8. [Crossref] [PubMed]
13. Vokes EE, Ready N, Felip E, et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol 2018;29:959-65. [Crossref] [PubMed]
14. Herbst RS, Garon EB, Kim DW, et al. Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1-Positive, Advanced Non-Small-Cell Lung Cancer in the KEYNOTE-010 Study. J Clin Oncol 2020;38:1580-90. [Crossref] [PubMed]
15. Postow MA, Sidlow R, Hellmann MD, et al. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-68. [Crossref] [PubMed]
16. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:1627-39. [Crossref] [PubMed]
17. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 2016;387:1540-50. [Crossref] [PubMed]
18. Middleton G, Brock K, Savage J, et al. Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. Lancet Respir Med 2020;8:895-904. [Crossref] [PubMed]
19. Felip E, Ardizzoni A, Ciuleanu T, et al. CheckMate 171: a phase 2 trial of nivolumab in patients with previously treated advanced squamous non-small cell lung cancer, including ECOG PS2 and elderly population. Eur J Cancer 2020;127:160-72. [Crossref] [PubMed]
20. Spigel DR, McCleod M, Jotte RM, et al. Safety, Efficacy, and Patient-Reported Health-Related Quality of Life and Symptom Burden with Nivolumab in Patients with Advanced Non-Small Cell Lung Cancer, Including Patients Aged 70 Years or Older or with Poor Performance Status (CheckMate 153). J Thorac Oncol 2019;14:1628-39. [Crossref] [PubMed]
21. Barlesi F, Audigier-Valette C, Felip E, et al. CheckMate 817: First-Line Nivolumab + Ipilimumab in Patients with ECOG PS 2 and Other Special Populations with Advanced NSCLC. J Thorac Oncol 2019;14:S214-5. [Crossref]
22. Roesel C, Kambartel K, Kopeika U, et al. Lazarus-type tumour response to therapy with nivolumab for sarcomatoid carcinomas of the lung. Curr Oncol 2019;26:e270-3. [Crossref] [PubMed]
23. Ettinger DS, Wood DE, Aggarwal C, et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020. J Natl Compr Canc Netw 2019;17:1464-72. [Crossref] [PubMed]
24. Inoue A, Kobayashi K, Usui K, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol 2009;27:1394-400. [Crossref] [PubMed]
25. Iwama E, Goto Y, Murakami H, et al. Alectinib for patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status (Lung Oncology Group in Kyushu 1401). J Thorac Oncol 2017;12:1161-6. [Crossref] [PubMed]
26. Passaro A, Spitaleri G, Gyawali B, et al. Immunotherapy in Non-Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence. J Clin Oncol 2019;37:1863-7. [Crossref] [PubMed]
27. Escoin-Perez C, Blasco S, Juan-Vidal O. Immune checkpoint inhibitors in special populations. A focus on advanced lung cancer patients. Lung Cancer 2020;144:1-9. [Crossref] [PubMed]
28. Pietrantonio F, Loupakis F, Randon G, et al. Efficacy and Safety of Immune Checkpoint Inhibitors in Patients with Microsatellite Instability-High End-Stage Cancers and Poor Performance Status Related to High Disease Burden. Oncologist 2020;25:803-9. [Crossref] [PubMed]
29. Pluvy J, Brosseau S, Naltet C, et al. Lazarus syndrome in nonsmall cell lung cancer patients with poor performance status and major leukocytosis following nivolumab treatment. Eur Respir J 2017;50:1700310. [Crossref] [PubMed]
30. McLoughlin EM, Larner JM, Bergman MP, et al. Rapid response to pembrolizumab in a critically ill mechanically ventilated patient with new diagnosis of NSCLC. J Thorac Oncol 2019;14:e193-5. [Crossref] [PubMed]
31. Frost N, Kollmeier J, Pultermann D, et al. Pembrolizumab as first-line treatment in NSCLC with PD-L1 ≥50%: real life results from an all-comer population. Ann Oncol 2019;30:V615. [Crossref]
32. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18:895-903. [Crossref] [PubMed]
33. Facchinetti F, Mazzaschi G, Barbieri F, et al. First-line pembrolizumab in advanced nonesmall cell lung cancer patients with poor performance status. Eur J Cancer 2020;130:155-67. [Crossref] [PubMed]
34. Shibaki R, Murakami S, Shinno Y, et al. Predictive value of serum VEGF levels for elderly patients or for patients with poor performance status receiving anti-PD-1 antibody therapy for advanced non-small-cell lung cancer. Cancer Immunol Immunother 2020;69:1229-36. [Crossref] [PubMed]
35. Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: A systematic review and meta-analysis. JAMA Oncol 2016;2:1607-16. [Crossref] [PubMed]
36. Spigel D, Schwartzberg L, Waterhouse D, et al. Is nivolumab safe and effective in elderly and PS2 patients with non-small cell lung cancer (NSCLC)? Results of CheckMate 153. J Thoracic Oncol 2017;12:S1287-8. [Crossref]
37. Su C, Zhou F, Shen J, et al. Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced Non-Small Cell Lung Cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations - Still a daily challenge. Eur J Cancer 2017;83:266-78. [Crossref] [PubMed]
38. Brahmer JR, Rodríguez-Abreu D, Robinson AG, et al. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024) a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol 2017;18:1600-9. [Crossref] [PubMed]
39. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376:2415-26. [Crossref] [PubMed]
40. Gyawali B, Prasad S, Feinberg BA, et al. Real-world evidence and randomized studies in the precision oncology era: The right balance. JCO Precis Oncol 2017. [Crossref]
41. Gauci ML, Marabelle A, Champiat S, et al. Long-Term Survival in Patients Responding to Anti-PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation. Clin Cancer Res 2019;25:946-56. [Crossref] [PubMed]

(English Language Editor: J. Gray)